ATM, the gene product mutated in the cancer susceptibility syndrome ataxia–telangiectasia, is related to proteins involved in DNA repair and cell-cycle control. It encodes a nuclear 350 kDa phosphoprotein containing a carboxy terminus phosphatidylinositol 3-kinase (Pl-3 kinase) catalytic domain shared by members of a superfamily of... Read more
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Akt family of serine/threonine-directed kinases regulates a diverse array of biological processes, including cellular survival, proliferation, glucose homeostasis, and vascular tone and are important molecules in mammalian cellular signaling. The three widely expressed isoforms of PKB (PKB , PKBß and PKB ; also known as Akt1, Akt2 and Akt3, respectively) are each composed of an N-terminal PtdIns(3,4,5)P3- and PtdIns(3,4)P2-binding PH domain and a C-terminal kinase catalytic domain. Stimulation by numerous growth factors, cytokines, hormones and neurotransmitters can activate PKB/Akt in a phosphoinositide 3-kinase-dependent manner. Through receptor tyrosine kinases, these stimuli cause phosphoinositide 3-kinase activation, and generation of the membrane phospholipid PtdIns(3,4,5)P3. PtdIns(3,4,5)P3 then recruits PKB/Akt to the membrane, where it becomes phosphorylated (for PKB/Akt1) by upstream kinases, phosphoinositide-dependent kinase 1. Following the activation of PI 3-kinase, PKB isoforms are recruited from the cytosol to the plasma membrane through their interaction with PtdIns(3,4,5)P3 and/or PtdIns(3,4)P2 where they are thought to undergo a conformational change and become activated by phosphorylation of two residues. PKB can promote cell survival by inhibiting proteins that mediate apoptosis. Phosphorylation of BAD by PKB (and other AGC kinases) enables it to interact with 14-3-3 proteins, which prevents it from binding to Bcl-XL and thereby suppresses apoptosis. It directly phosphorylate and inhibit the caspase proteasesm, key executioners of apoptosis. PKBbeta, an essential gene for the maintenance of normal glucose homeostasis and is likely to represent a critical intermediate in the insulin signal transduction pathway. PKB activation might inhibit apoptosis by promoting the increased expression of survival molecules or the degradation of pro-apoptotic molecules. PKB also phosphorylates and activates endothelial nitric oxide synthase, thereby promoting angiogenesis (formation of new blood vessels). Inhibition of GSK3 following its phosphorylation by PKB has also been suggested to play a role in inhibiting apoptosis in neuronal cells. Thus it plays a key role in cancer progression by stimulating cell proliferation and inhibiting apoptosis, which suggests it, likely to be a hot drug target for the treatment of cancer, diabetes and stroke.
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